The present work continues prior investigation of insulin receptors on circulating cells in patients with insulin resistance and diabetes mellitus. Insulin receptors are evaluated for their ability to bind insulin and to act as tyrosine-specific protein kinases. The insulin receptor of a patient with Type A extreme insulin resistance who has normal insulin binding but abnormal tyrosine kinase activity has been sequenced and a mutation found in the extracellular portion of the beta subunit. We have also showed a strong correlation between the ability of purified anti-insulin receptor antibodies from patients with Type B extreme insulin resistance to inhibit insulin binding and immunoprecipitate the insulin receptor. The correlation of these activities with the biologic activity of the antibodies is not predictable.